Pharmaceutical compositions and methods for anesthesiological applications

ABSTRACT

Pharmaceutical compositions and methods for inducing conscious sedation using such compositions are described, the compositions including a benzodiazepine-based compound, a NMDA antagonist, and optionally a β-blocker, antiemetic, an NSAID, and/or an antihistamine medication. Methods for fabricating the compositions and using them for anesthesiological applications are also described.

CROSS REFERENCE TO RELATED APPLICATION(S)

This is a continuation-in-part patent application under 35 U.S.C. § 120to U.S. patent application Ser. No. 15/184,768, filed Jun. 16, 2016, nowpending, which in turn claims the benefit of priority under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62/182,130, filed Jun. 19,2015, the entire content of each of which is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates generally to the field of pharmacology andmore specifically to compositions having anesthetic properties that areuseful in various kinds of surgery, e.g., ophthalmic surgery, and tomethods of preparing and using such compositions.

BACKGROUND

The present disclosure relates to solid or liquid pharmaceuticalformulations comprising combinations of active agents such asanesthetics, anti-emetics, blood pressure, anti-anxiety medicationsand/or analgesics, and methods for using the same for providinganesthesia by administering such compositions orally, e.g., sublinguallyor bucally. The formulations may also include slow release reversalagents that would counteract the initial anesthesia effect.

It is necessary in many cases to use local anesthesia, particularly viaoral route in the course of various surgical procedures, e.g.,ophthalmic surgeries or urological interventions. For instance, whenlocal anesthesia is employed during or prior to intraocular operations,the occurrences of pain, anxiety, peri-operative stress, nausea,agitation, vomiting and the like are less frequent, which will typicallyhave a very beneficial effect on the surgical experience and reducingthe number of intraocular complications such as bleeding, secretions,cardiac and/or pulmonary complications, etc. The severity of thosecomplications when they do occur will also be less pronounced when localanesthesia is used.

Traditionally intravenous route is used to administer medications.Alternatives to intravenous methods and therapies have been suggestedand previously used for the treatment. In particular, oraladministration of benzodiazepines, opioid analgesics, propofol, ketamineor etomidate utilizing the MAC procedure (monitored anesthesia care) hasbeen suggested and tried, but no more than minimal to moderateimprovement has been achieved by such methods. Therefore, there remainsa need for better treatments of these disorders.

This patent specification discloses such pharmaceutical compositionssuitable for anesthesiological applications that can achieve positivepatient outcomes while free of drawbacks and deficiencies of existingmethods and formulations. Methods of fabricating and administering thesame are also discussed.

SUMMARY

According to one embodiment of the invention, there are providedpharmaceutical compositions. The compositions include a therapeuticallyeffective quantity of at least one first pharmaceutically activecompound comprising benzodiazepine moiety or pharmaceutically acceptablesalts, hydrates, solvates or N-oxides thereof, a therapeuticallyeffective quantity of at least one second pharmaceutically activecompound that is an NMDA antagonist or pharmaceutically acceptablesalts, hydrates, solvates or N-oxides thereof, and at least onepharmaceutically acceptable excipient or carrier therefor.

According to another embodiment of the invention, the pharmaceuticalcompositions described above may further include a therapeuticallyeffective quantity of at least one third pharmaceutically activecompound that is a β-blocker, a nonsteroidal anti-inflammatory drug(NSAID), or an antiemetic medicament, or a combination thereof, orpharmaceutically acceptable salts, hydrates, solvates or N-oxidesthereof.

According to further embodiments of the invention, in the pharmaceuticalcompositions described above, the first pharmaceutically active compoundmay be any of midazolam, diazepam, lorazepam, flunitrazepam, alprazolam,chlordiazepoxide, clonazepam or clorazepate, the second pharmaceuticallyactive compound may be any of ketamine, dextrorphan, etomidate,methadone, memantine, amantadine or dextromethorphan and the thirdpharmaceutically active compound may be (if a β-blocker) any ofmetoprolol, propranolol, acebutolol, nadolol, atenolol, betaxolol,esmolol, bisoprolol fumarate, carvedilol, nebivolol, penbutolol,timolol, or sotalol or (if an antiemetic) ondansentron, dolasetron,granisetron, palonosetron, promethazine, imenhydrinate, or meclizine.

According to yet another embodiment of the invention, there are providedfurther pharmaceutical compositions such as any described above, whereinthe compositions are formulated as a liquid or a solid item, e.g., atroche, a lozenge, a capsule, a pill, a cap and a bolus suitable forsublingual or oral administration.

According to other embodiments, there are provided specific compoundsfor making the compositions described above, for example, midazolam,ketamine and ondansetron, as well as methods for using above-mentionedcomposition(s) for the purposes of local anesthesia in variousapplications, such as ophthalmic surgery.

According to further embodiments of the invention, the above-mentionedmethods of using the composition(s) include orally administering to apatient in need thereof (i.e., those patients who require conscioussedation or pre-sedation) a pharmaceutical composition described hereinas the first step of a medical or surgical procedure, the procedurebeing an ophthalmic surgery (e.g., a cataract, glaucoma, corneal, eyelidsurgery, or retinal surgery), a dental procedure (e.g., a toothextraction, an oral surgery, or a root canal surgery), an outpatientmedical procedure (e.g., medical imaging procedure, biopsy, bone marrowharvesting, colonoscopy, or endoscopy), a urological procedure, alaparoscopic procedure, obstetric and gynecological procedures, agastrointestinal procedure, an otolaryngological procedure, a cosmeticsurgery procedure, a dermatological procedure, a podiatric procedure, anorthopedic procedure, an emergency medical treatment, a psychiatrictreatment, or a veterinarian procedure.

DETAILED DESCRIPTION A. Terms and Definitions

Unless specific definitions are provided, the nomenclatures utilized inconnection with, and the laboratory procedures and techniques ofanalytical chemistry, synthetic organic and inorganic chemistrydescribed herein, are those known in the art. Standard chemical symbolsare used interchangeably with the full names represented by suchsymbols. Thus, for example, the terms “hydrogen” and “H” are understoodto have identical meaning. Standard techniques may be used for chemicalsyntheses, chemical analyses, formulating compositions and testing them.The foregoing techniques and procedures can be generally performedaccording to conventional methods well known in the art.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise. The section headings used herein are for organizationalpurposes only and are not to be construed as limiting the subject matterdescribed.

As used herein, “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“includes,” and “included,” is not limiting.

“About” as used herein means that a number referred to as “about”comprises the recited number plus or minus 1-10% of that recited number.For example, “about” 100 degrees can mean 95-105 degrees or as few as99-101 degrees depending on the context. Whenever it appears herein, anumerical range such as “1 to 20” refers to each integer in the givenrange; i.e., meaning only 1, only 2, only 3, etc., up to and includingonly 20.

The term “pharmaceutical composition” is defined as a chemical orbiological compound or substance, or a mixture or combination of two ormore such compounds or substances, intended for use in the medicaldiagnosis, cure, treatment, or prevention of disease or pathology.

The terms “anesthetic,” “anesthesia,” “anesthesiology” and the likerefer herein to substances, compounds, processes or procedures thatinduce insensitivity to pain such as a temporary loss of sensation.

The term “conscious sedation” that for the purposes of this applicationmay be used interchangeably with terms “procedural sedation” and“analgesia” is used herein to refer to an induced state of sedationcharacterized by a minimally depressed consciousness such that thepatient is able to continuously and independently maintain a patentairway, retain protective reflexes, and remain responsive to verbal cuesand/or tactile or physical stimulation.

Conscious sedation is typically performed/induced to decrease the levelof anxiety in a patient and to elicit an improved degree of cooperationfrom the patient prior to or during a procedure. Conscious sedation,therefore, refers to a condition that is medically different anddistinct from deep sedation which is the next level of sedation definedas depression of consciousness when the patient's ability toindependently maintain ventilatory function may be impaired and he orshe cannot be easily aroused; however, the patient will stillpurposefully respond to repeated or painful stimulation.

Conscious sedation is also clearly distinguishable for the purposes ofthe present application from the lower level of sedation (i.e., minimalsedation when the patient is able to maintain a normal response toverbal stimuli) as well as the highest level of sedation (i.e., generalanesthesia when there is no response from the patient even with painfulstimulus).

The term “pre-sedation” is defined for the purposes of this applicationas conscious sedation that is induced some time before a procedure, e.g,between 5 minutes and 1 hour prior.

The terms “solvate” and “hydrate” are used herein to indicate that acompound or substance is physically or chemically associated with asolvent for “solvates” such as water (for “hydrates”).

The term “NMDA antagonist” is defined as a compound that inhibits(“antagonizes”) the action of the N-methyl-D-aspartate receptors and isinclusive of both competitive and non-competitive antagonists, glycineantagonists and uncompetitive channel blockers, as these terms areunderstood by those having ordinary skill in the art.

The term “β-blocker” refers to a compound of any kind that can preventor reduce the stimulation of the adrenergic receptors responsible forincreased cardiac action.

The term “antiemetic” is defined as a drug or medicament that treats,reduces, and/or prevents nausea and/or vomiting.

The term “non-steroid anti-inflammatory drug” or “NSAID” refers to aclass of compounds that are free of any steroid moieties yet are capableof providing analgesic, antipyretic and/or anti-inflammatory effects.

The term “antihistamine medicament” refers to any compound that iscapable of inhibiting or counteracting the physiological effects ofhistamine.

The term “polyglycol” is defined as a polymer or oligomer containingseveral ether-glycol linkages that yields one or more glycols when theselinkages are cleaved, e.g., by hydrolysis.

The term “carrier” refers to a substance that serves as a vehicle forimproving the efficiency of delivery and the effectiveness of apharmaceutical composition.

The term “excipient” refers to a pharmacologically inactive substancethat is formulated in combination with the pharmacologically activeingredient of pharmaceutical composition and is inclusive of bulkingagents, fillers, diluents and products used for facilitating drugabsorption or solubility or for other pharmacokinetic considerations.

The term “binder” refers to a substance or compound that promotes,provides or improves cohesion, i.e., a substance that causes thecomponents of a mixture to cohere to form a solid item that possessesintegrity.

The term “troche” refers to a small tablet or lozenge (i.e., a medicatedcandy intended to be dissolved in the mouth), typically in a form of adisk, a ball or rhombic in cross-section, comprising medication andprocessed into a paste and dried.

The term “therapeutically effective amount” is defined as the amount ofthe compound or pharmaceutical composition that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, medical doctor or other clinician.

The term “pharmaceutically acceptable” when used in the context of acarrier, diluent or excipient, refers to a substance that is compatiblewith the other ingredients of the formulation and not deleterious to therecipient thereof.

The terms “administration of a composition” or “administering acomposition” is defined to include an act of providing a compound of theinvention or pharmaceutical composition to the subject in need oftreatment.

The terms “oral administration” and “orally administering” are broadlydefined as a route of administration where a medication is taken throughthe mouth including “sublingual administration” and “buccaladministration” where the medication is placed under the tongue orbetween the gums and the cheek, respectively, to be absorbed by thebody, or to be administered sublingually or buccally as a liquid.

B. Embodiments of the Invention

According to embodiments of the present invention, there are providedpharmaceutical compositions for anesthetic purposes. The compositionscomprise, consist of or consist essentially of, a combination oftherapeutically effective quantities of at least one firstpharmaceutically active compound and at least one secondpharmaceutically active compound. In some further embodiments, thecompositions optionally comprise, in addition to the above-mentionedfirst and second pharmaceutically active compounds, at least one thirdpharmaceutically active compound.

The first pharmaceutically active compound that is used in suchcomposition comprises a benzodiazepine moiety or pharmaceuticallyacceptable salts, hydrates, solvates or N-oxides thereof. Those havingordinary skill in the art will know that benzodiazepine moiety is astructure where a benzene ring is condensed with diazepine ring, aseven-member heterocycle with two nitrogen atoms which for the purposesof this specification may be in any positions of the ring (e.g.,1,2-diazepine, 1,3-diazepine or 1,4-diazepine). An example of a compoundhaving benzodiazepine moiety with 1,4-diazepine structure is shownbelow:

One particular first pharmaceutically active compound comprising abenzodiazepine moiety that can be used in pharmaceutical compositionsdescribed and claimed herein is midazolam. Other specific, non-limitingexamples of first pharmaceutically active compounds comprisingbenzodiazepine moiety that can be used include diazepam, lorazepam,flunitrazepam, alprazolam, chlordiazepoxide, clonazepam, clobazam,bromazepam, prazepam, oxazepam and clorazepate. Each of these is alsoknown under one or several trade names as shown in Table 1, which alsodiscloses chemical names of such compounds. Those having ordinary skillin the art can select alternative suitable benzodiazepine-based compoundfor using in the compositions, if so desired.

TABLE 1 Examples of Benzodiazepine-Based Compounds That Can Be Used inCompositions Compound Chemical Name (IUPAC) Trade Name(s) Midazolam8-chloro-6-(2-fluorophenyl)-1-methyl-4H- VERSED ®, DORMICUM ®,imidazo[1,5-a][1,4]benzodiazepine HYPNOVEL ® Diazepam7-chloro-1-methyl-5-phenyl-3H-1,4- VALIUM ®, DIASTAT ®benzodiazepin-2-one Lorazepam 7-chloro-5-(2-chlorophenyl)-3-hydroxy-TEMESTA ®, ATIVAN ®, 1,3-dihydro-2H-1,4-benzodiazepin-2-one ORFIDAL ®Flunitrazepam 5-(2-fluorophenyl)-1-methyl-7-nitro-1H- ROHYPNOL ®,NARCOZEP ® benzo[e][1,4]diazepin-2(3H)-one and many others Alprazolam8-chloro-1-methyl-6-phenyl-4H- XANAX ®[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Chlordiazepoxide7-chloro-2-methylamino-5-phenyl-3H-1,4- LIBRIUM ® benzodiazepine-4-oxideClonazepam 5-(2-chlorophenyl)-7-nitro-2,3-dihydro- KLONOPIN ®,RIVOTRIL ® and 1,4-benzodiazepin-2-one many others Clorazepate7-chloro-2,3-dihydro-2-oxo-5-phenyl- TRANXENE ®1H-1,4-benzodiazepine-3-carboxylic acid Bromazepam7-bromo-5-(pyridin-2-yl)-1H- LEXOTAN ®, LEXOTANIL ®benzo[e][1,4]diazepin-2(3H)-one and many others Oxazepam7-chloro-3-hydroxy-5-phenyl-2,3-dihydro- ALEPAM ®, SERAX ® and many1H-1,4-benzodiazepine-2-one others Clobazam7-chloro-1-methyl-5-phenyl-1,5- URBANOL ®, FRISIUM ®,benzodiazepine-2,4(3H)-dione ONFI ® Prazepam7-chloro-1-(cyclopropylmethyl)-5-phenyl- LYSANXIA ®, CENTRAX ® and1,3-dihydro-2H-1,4-benzodiazepin-2-one many others

The therapeutically effective quantity of the benzodiazepine-basedcompound(s) in the entire pharmaceutical composition can be betweenabout 0.2 mass % and about 5.0 mass % of the composition. In someembodiments, the therapeutically effective amount of thebenzodiazepine-based compound(s) can be between about 1.0 mass % andabout 3.0 mass %, for example, about 2.5 mass % of the composition.

In some applications a patient may be extra sensitive to benzodiazepines(e.g., may become excessively drowsy). For such patients, there areprovided additional embodiments of the composition in whichbenzodiazepine(s)-containing pharmaceutical compositions describedabove, would additionally include a quantity of a receptor antagonist tobenzodiazepines. Such a receptor antagonist would begin counteractingthe effect of benzodiazepine after the surgical procedure is complete,in essence providing a slow release feature. A non-limiting example ofthis antagonist is flumazenil also known under trade names such asANEXATE®, ROMAZICON® and others. The use of antagonists is alsoenvisioned as a routine practice (i.e., not just for sensitivepatients), for example, in situations when a larger than typical orusual dosage of benzodiazepines is medically indicated, or recommended,or necessary. In some further applications, benzodiazepine-basedcompounds may be used in combination with non-benzodiazepine basedsedatives such as eszopiclone, ramelteon, zolpidem, or zaleplon.

The second pharmaceutically active compound that is used in suchcompositions is an NMDA antagonist, as defined hereinabove, orpharmaceutically acceptable salts, hydrates, solvates or N-oxidesthereof. One particular second pharmaceutically active compound that canbe used in pharmaceutical compositions described and claimed herein isketamine. Other specific, non-limiting examples of NMDA antagonists thatcan be used include dextrorphan, etomidate, methadone, memantine,amantadine and dextromethorphan. Each of these is also known under oneor several trade names as shown in Table 2, which also discloseschemical names of such compounds. Those having ordinary skill in the artcan select alternative suitable NMDA antagonists for using in thecompositions, if so desired.

TABLE 2 Examples of NMDA Antagonists That Can Be Used in CompositionsCompound Chemical Name (IUPAC) Trade Name(s) Ketamine2-(2-chlorophenyl)-2-(methylamino)cyclohexanone KETANEST ®, KETASET ®,KETALAR ® (HCl salt) Dextrorphan 17-methyl-9a,13a,14a-morphinan-3-olNone Etomidate Ethyl-3-[(1R)-1-phenylethyl]imidazole-5-carboxylateAMIDATE ®, HYPNOMIDATE ® Methadone6-(dimethylamino)-4,4-diphenylheptan-3-one DOLOPHINE ®, AMIDONE ® andothers Memantine 3,5-dimethyladamantan-1-amine AKATINOL ®, NAMENDA ® andothers Amantadine Adamantan-1-amine SYMMETREL ® Dextromethorphan(4bS,8aR,9S)-3-methoxy-11-methyl-6,7,8,8a,9,10- ROBITUSSIN ®,hexahydro-5H-9,4b-(epiminoethano)phenanthrene DELSYM ® and others

The therapeutically effective quantity of the NMDA antagonist(s) in theentire pharmaceutical composition can be between about 1.0 mass % andabout 10.0 mass % of the composition. In some embodiments, thetherapeutically effective amount of the NMDA antagonist(s) can bebetween about 4.0 mass % and about 6.0 mass %, for example, about 5.0mass % of the composition. Accordingly, in various embodiments, thecombined quantities of both the benzodiazepine-based compound(s) and theNMDA antagonist(s), taken together, in the entire pharmaceuticalcomposition can be between about 1.2 mass % and about 15.0 mass % of thecomposition, such as between about 3.0 mass % and about 12.0 mass %, forexample, about 10.0 mass % of the composition.

As mentioned above, the compositions may further optionally include atleast one third pharmaceutically active compound. In such embodiments,the third pharmaceutically active compound is a β-blocker, as definedhereinabove, or pharmaceutically acceptable salts, hydrates, solvates orN-oxides thereof, or alternatively, and α-2-adrenergic agonist or, asanother alternative, a pain reliever. In addition to, or instead of,β-blockers, the third pharmaceutically active compound may also includean antiemetic medicament, as defined hereinabove, or pharmaceuticallyacceptable salts, hydrates, solvates or N-oxides thereof.

In yet another aspect, the third pharmaceutically active compound mayinclude one or several non-steroid anti-inflammatory drug(s) (NSAIDs),as defined hereinabove. NSAID(s) may be so used in addition to, orinstead of, β-blocker(s), and/or antiemetic(s). In a further aspect, thethird pharmaceutically active compound may also include an antihistaminemedicament, as defined hereinabove. Non-limiting examples of specificantihistamine medicaments that can be so used include, but are notlimited to, any of hydroxyzine pamoate, hydroxyzine hydrochloride,diphenhydramine hydrochloride, meclizine, chlorpheniramine, clemastine,promethazine, or prochlorperazine, or any combination thereof. Again,antihistamine medicaments may be used in addition to, or instead of, anyof the above-mentioned compounds that may be used as the thirdpharmaceutically active compound.

The therapeutically effective quantity of the third pharmaceuticallyactive compound(s) in the entire pharmaceutical composition can bebetween about 0.1 mass % and about 5.0 mass % of the composition. Insome embodiments, the therapeutic effective amount of the thirdpharmaceutically active compound(s) can be between about 1.0 mass % andabout 4.0 mass %, for example, about 2.5 mass % of the composition.

One particular β-blocker that can be used as the third pharmaceuticallyactive compound in pharmaceutical compositions described and claimedherein is metoprolol. Other specific, non-limiting examples ofβ-blockers or α-2-adrenergic agonists or pain relievers that can be usedinclude, propranolol, acebutolol, nadolol, atenolol, betaxolol, esmolol,bisoprolol fumarate, carvedilol, nebivolol, penbutolol, timolol,sotalol, dexmedetomidine hydrochloride, and acetaminophen. Each of theseis also known under one or several trade names as shown in Table 3,which also discloses chemical names of such compounds. Those havingordinary skill in the art can select alternative suitable β-blockers forusing in the compositions, if so desired.

TABLE 3 Examples of β-Blockers That Can Be Used in Compositions CompoundChemical Name (IUPAC) Trade Name(s) Metoprolol1-(isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol LOPRESSOR ®,TOPROL ® Propranolol 1-(1-methylethylamino)-3-(1-naphthyloxy)propan-2-olCIPLA ®, INDERAL ® and many others AcebutololN-{3-acetyl-4-[2-hydroxy-3-(propan-2-ylamino) SECTRAL ®,propoxy]phenyl}butanamide PRENT ® Nadolol5-{[3-(tert-butylamino)-2-hydroxypropyl]oxy}-1,2,3,4- CORGARD ®tetrahydronaphthalene-2,3-diol Atenolol2-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy] TENORMIN ® phenyl}acetamideBetaxolol 1-{4-[2-(cyclopropylmethoxy)ethyl]-phenoxy}-3- KERLONE ®,(isopropylamino)propan-2-ol BETOPTIC ® and others Esmolol3-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy] BREVIBLOC ®phenyl}propanoate Bisoprolol1-[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]-3[(1- ZEBETA ® fumaratemethylethyl)amino]-2-propanol-2-butenedioate Carvedilol3-(9H-carbazol-4-yloxy)-2-hydroxypropyl-2-(2- COREG ®,methoxyphenoxy)ethylamine CARVIL ® and many other Nebivolol2,2′-azanediylbis(1-(6-fluorochroman-2-yl)ethanol) NEBILET ®, BYSTOLIC ®Penbutolol 1-(tert-butylamino)-3-(2-cyclopentylphenoxy)propan-2-olLEVATOL ®, LEVATOLOL ® and many others Timolol1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3- TIMOPTIC ®,yl)oxy]propan-2-ol BETIMOL ® and many others SotalolN-{4-[1-hydroxy-2-(propan-2-ylamino)ethyl]phenyl} BETAPACE ® andmethanesulfonamide others

One particular antiemetic that can be used as the third pharmaceuticallyactive compound in pharmaceutical compositions described and claimedherein is ondansetron. Other specific, non-limiting examples ofantiemetics that can be used include dolasetron, granisetron,palonosetron, promethazine, imenhydrinate, and meclizine. Each of theseis also known under one or several trade names as shown in Table 4,which also discloses chemical names of such compounds. Those havingordinary skill in the art can select alternative suitable antiemeticsfor using in the compositions, if so desired.

TABLE 4 Examples of Antiemetics That Can Be Used in CompositionsCompound Chemical Name (IUPAC) Trade Name(s) Ondansetron(RS)-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-2,3- ZOFRAN ®,dihydro-1H-carbazol-4(9H)-one ONDISOLV ® Dolasetron(2α,6α,8α,9aβ)-octahydro-3-oxo-2,6-methano-2H-quinolizin- ANZEMET ®8-yl-1H-indole-3-carboxylate monomethanesulfonate, monohydrateGranisetron 1-methyl-N-((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-KYTRIL ® yl)-1H-indazole-3-carboxamide Palonosetron(3aS)-2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6- ALOXI ®hexahydro-1H-benz[de]isoquinolin-1-one Promethazine(RS)-N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2- PHENERGAN ® amineDimenhydrinate 2-benzhydryloxy-N,N-dimethylethanamine; 8-chloro-1,3-DRAMAMINE ®, dimethyl-7H-purine-2,6-dione GRAVOL ®, VOMEX ®, many othersMeclizine (RS)-1-[(4-chlorophenyl)(phenyl)methyl]-4-(3- BONINE ®,methylbenzyl)piperazine BONAMINE ®, ANTIVERT ®, many others

Therefore, in various embodiments, the combined quantities of all thepharmaceutically active compounds (i.e., the benzodiazepine-basedcompound(s), the NMDA antagonist(s), the (3-blocker(s)), and/or theantiemetic(s) taken together, in the entire pharmaceutical compositioncan be between about 1.3 mass % and about 20.0 mass % of thecomposition, such as between about 3.0 mass % and about 12.0 mass %, forexample, about 10.0 mass % of the composition. Those having ordinaryskill in the art will determine the most appropriate quantities of eachthe pharmaceutically active compound that are within the above-mentionedranges and that are most suitable for a particular patient. As anon-limiting guideline only, the following mass ratios between thepharmaceutically active compounds may be used (Table 5) for compositionswhere the benzodiazepine-based compound is midazolam, the NMDAantagonist is ketamine hydrochloride and the β-blocker is propanololhydrochloride:

TABLE 5 Exemplary Mass Ratios between Midazolam, Ketamine Hydrochlorideand Propanolol Hydrochloride in the Compositions Ketamine PropanololRatios Midazolam Hydrochloride Hydrochloride Between about 1 2 1 andabout 1 10 1 Such as between about 1 4 1 and about 1 6 1 For example 1 51

In one specific embodiment, which is exemplary and non-limiting, for thecomposition having midozalam as the first pharmaceutically activecompound, ketamine as the second pharmaceutically active compound andondansentron at the third pharmaceutically active compound, the massmidazolam:ketamine:odansentron ratio may be about 3:25:2.

The pharmaceutical compositions described herein may contain not onlypharmaceutically active components but also, in some embodiments, mayfurther include one or several inactive, neutral compounds which can bepharmaceutically acceptable excipient(s) or carrier(s), including, butnot limited to, binder(s), antioxidant(s), adjuvant(s), synergist(s)and/or preservative(s). The mass concentration of such inactivecompounds can be between about 80 mass % and about 99 mass % of theentire pharmaceutical composition, such as between about 85 mass % andabout 95 mass %, e.g., about 90 mass %.

Some embodiments of the invention are directed to pharmaceuticalformulations that are formulated as solid articles suitable forsublingual or oral administration, such as troches, lozenges, capsules,pills, caps or boluses. These solid compositions typically comprisebinder(s) and/or excipient(s). They can be prepared by first mixing thepharmaceutically active compounds described above with suitablebinder(s) and/or excipient(s) followed by molding or compressing theblend. Both hard and chewable lozenges and troches are within the scopeof the invention.

Typical binder(s) that can be used for fabricating solid articlesmentioned above include, without limitation, polyglycols as definedabove, such as, e.g., polyethylene glycols (PEGs), polyethylene oxides(POE), methoxypolyethylene glycols, polypropylene glycols, polybutyleneglycols or derivatives thereof having a molecular weight that issufficient to provide the necessary hardness and time for dissolution ofthe troche; for example, the acceptable molecular weight can be withinthe range of between about 1,000 Daltons and about 8,000 Daltons. Insome embodiments PEG-1450 or PEG-400 can be used. Non-limiting examplesof some specific polyglycol derivatives that can be used are:

-   -   (a) PEG-laureates and dilaureates (e.g., PEG-10-, PEG-12-,        PEG-20-, PEG-32-laurates, PEG-20- and PEG-32-dilaurates,        PEG-20-glyceryl-, PEG-30-glyceryl- and PEG-40-glyceryl-laurates,        PEG-80-sorbitan laurate);    -   (b) PEG-oleates, dioleates and trioleates (e.g., PEG-12-,        PEG-15-, PEG-20-, PEG-32, PEG-200- and PEG-400-oleates, PEG-20-        and PEG-32-dioleates, PEG-20-trioleate, PEG-25-glyceryl        trioleate, PEG-20-glyceryl- and PEG-30-glyceryl-oleates,        PEG-40-sorbitan oleate);    -   (c) PEG-stearates and distearates (e.g., PEG-15-, PEG-40-,        PEG-100-stearates, PEG-32-distearate and PEG-20-glyceryl        stearate)    -   (d) castor, palm kernel, corn and soya oil derivatives of PEG        (e.g., PEG-35-, PEG-40- and PEG-60-castor oils, PEG-40-, PEG-50-        and PEG-60-hydrogenated castor oils, PEG-40-palm kernel oil,        PEG-60-corn oil, PEG-30-soya sterol);    -   (e) other PEG derivatives (e.g., PEG-24- and PEG-30-cholesterol,        PEG-25-phytosterol, PEG-6- and PEG-8-caprate/caprylate        glycerides, tocopheryl PEG-100 succinate, PEG-15-100 octylphenol        products and PEG-10-100 nonylphenol products);    -   (f) other products such as polyglyceryl-10-laurate, POE-9- and        POE-23-lauryl ethers, POE-10- and POE-20-oleyl ethers,        POE-20-stearyl ether, polysorbates-20 and 80,        polyglyceryl-10-oleate, Tween 40, Tween 60, sucrose        monostearate, monolaurate and monopalmitate and various products        of Poloxamer series.

Typical excipient(s) that can be used for fabricating solid articlesmentioned above include, without limitation, gelatin, sodium saccharin,stevioside, peppermint oil, or any natural or artificial fruit,vegetable, flower, beverage or candy flavor.

As stated above, the compositions may optionally further comprise one orseveral antioxidant(s). If antioxidant(s) are used, non-limitingexamples of those that can be used include α-tocopherol acetate, acetonesodium bisulfite, acetylcysteine, ascorbic acid, ascorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, cysteine, cysteinehydrochloride, tocopherol natural, tocopherol synthetic, dithiothreitol,monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodiumbisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodiumsulfite, sodium thiosulfate, thiourea and tocopherols.

As stated above, the compositions may optionally further include one orseveral adjuvant(s) or synergists(s). If adjuvant(s) or synergists(s)are used, non-limiting examples of those that can be used include citricacid, EDTA (ethylenediaminetetraacetate) and salts, hydroxyquinolinesulfate, phosphoric acid and tartaric acid.

As stated above, the compositions may optionally further include one orseveral preservative(s). If preservative(s) are used, non-limitingexamples of those that can be used include benzalkonium chloride,benzethonium chloride, benzoic acid and salts, benzyl alcohol, boricacid and salts, cetylpyridinium chloride, cetyltrimethyl ammoniumbromide, chlorobutanol, chlorocresol, chorhexidine gluconate orchlorhexidine acetate, cresol, ethanol, imidazolidinyl urea, metacresol,methylparaben, nitromersol, o-phenyl phenol, parabens, phenol,phenylmercuric acetate/nitrate, propylparaben, sodium benzoate, sorbicacids and salts, β-phenylethyl alcohol and thimerosal.

The pharmaceutical formulation can be administered to a subject in needof conscious sedation, procedural sedation, analgesia and/orpre-sedation, and in general for any kind of non-general anesthesia, byvarious local administrations. More specifically, the pharmaceuticalformulations described herein may be prescribed by ordinarily skilledmedical practitioners such as physicians, as the means of conscioussedation or pre-sedation. This is intended to be used for certainpatients who experience or expect to experience high anxiety, bouts ofpanic attacks, disquietude, apprehension, angst or similar feelings ofpsychological discomfort or distress prior to, or during, medical orsurgical procedures as described in more detail below. The patients maybe of any age, i.e., including children, adolescents and adults.

For example, the formulation can be used prior to various outpatientsurgeries and medical procedures, both invasive and non-invasive, suchas an ophthalmic surgery, outpatient medical or surgical procedures,dental procedures, urological procedures, obstetric and gynecologicalprocedures, gastrointestinal procedures, otolaryngological procedures,cosmetic surgery procedures, dermatological procedures, podiatricprocedures, orthopedic procedures, emergency medical treatments,psychiatric treatments, and veterinarian procedures.

Specific representative examples of the procedures that are amenable touse of the formulation include, without limitation, cataract surgery,glaucoma surgery, corneal surgery, eyelid surgery, retinal surgery,tooth extraction, oral surgery, root canal surgery, medical imagingprocedures (e.g., MRI or CAT scanning, especially for patients sufferingfrom claustrophobia), biopsy, bone marrow harvesting, colonoscopy,endoscopy and laparoscopy.

In one non-limiting embodiment, the local administration is by oralroute, such as sublingually or buccally, typically being delivered tothe patient via a solid delivery vehicle such as a troche, a lozenge, acapsule, a pill, a cap, and a bolus, as mentioned above. In anadditional embodiment, the pharmaceutical composition may be formulatedas a liquid item adapted for sublingual or buccal administration (inwhich case it will include all the pharmaceutically active compoundsdescribed above, but no pharmaceutically suitable binder); such liquidformulations may be delivered by any method to be selected by one havingordinary skill in the art of delivery of medications, e.g., via asyringe or a pipette. Such local administration may be used instead orintravenous administration or to complement the latter, as appropriate.

It will be understood by those having ordinary skill in the art that thespecific dose level and frequency of dosage for any particular patientmay be varied and will depend upon many factors including the activityof the specific compound employed, the metabolic stability and length ofaction of that compound, the age, body weight, general health, gender,diet and the severity of the particular condition being treated.

According to further embodiments, methods for fabricating theabove-described pharmaceutical compositions are provided. A one-batchformulation method may be used, where the components of thepharmaceutical formulation can be combined in single container; thecomponents may be added to the container simultaneously orconsecutively. Alternatively, a two- or multiple-batch method(s) may beused if desired, where each component of the pharmaceutical formulationcan be combined in separate container followed by combining the contentsof each container.

In one exemplary, non-limiting procedure, pre-measured quantities ofeach ingredient in the form of dry powder can be mixed to form a dryblend followed by mixing it with a pre-molten troche base. Thecomposition can then be molded to form a troche.

In additional embodiments, pharmaceutical kits are provided. The kitincludes a sealed container approved for the storage of solidpharmaceutical compositions, the container containing one of theabove-described pharmaceutical compositions an instruction for the useof the composition and the information about the composition are to beaffixed to the container or otherwise enclosed with it.

The following examples are provided to further elucidate the advantagesand features of the present invention, but are not intended to limit thescope of the invention. The examples are for the illustrative purposesonly. USP pharmaceutical grade products were used in preparing theformulations described below.

Example 1. Preparing a Pharmaceutical Composition in the Form of aTroche

A pharmaceutical composition may be prepared as described below. Thefollowing products can be used in the amounts and concentrationsspecified:

-   -   (a) about 0.2 g of midazolam;    -   (b) about 2.0 g of ketamine hydrochloride;    -   (c) about 0.2 g of ondansetron hydrochloride;    -   (d) about 1 mL of lemon oil flavoring; and    -   (e) about 15.5 g of standard troche base (comprising polyglycol        1450, polyglycol 400, gelatin, sodium saccharin and steviaside).

The troche base can be melted at low heat while being stirred; whencompletely molten, the heat can be turned off with continued stirring.All the dry ingredients, pre-weighed can be added into the molten basefollowed by adding the flavoring and mixing all components together.

While any shape may be used, a half-moon shaped troche mold can belightly sprayed with PAM® (or a suitable oil/releasing agent) to coverthe entire surface of the mold and the mixture prepared as explainedabove can then be poured into the mold and allowed to cool and harden atroom temperature. A heat gun can then be used to smooth out the surfacefollowed by another round of cooling at room temperature followed byremoving the so prepared troche from the mold, placing it into aprescription vial and labeling the vial. The troche is now ready to beadministered.

Although the invention has been described with reference to the aboveexamples, it will be understood that modifications and variations areencompassed within the spirit and scope of the invention. Accordingly,the invention is limited only by the following claims.

What is claimed is:
 1. A method for carrying out an invasive or anon-invasive medical procedure, comprising orally administering to apatient in need of conscious sedation, procedural sedation, analgesia,pre-sedation or a non-general anesthesia a pharmaceutical composition asthe first step of the procedure, the pharmaceutical compositioncomprising: (a) a therapeutically effective quantity of a firstpharmaceutically active compound selected from the group consisting ofmidazolam, diazepam, lorazepam, flunitrazepam, alprazolam,chlordiazepoxide, clonazepam and clorazepate, and pharmaceuticallyacceptable salts, hydrates, solvates or N-oxides thereof; (b) atherapeutically effective quantity of a second pharmaceutically activecompound selected from the group consisting of ketamine, dextrorphan,etomidate, methadone, memantine, amantadine, dextromethorphan, andpharmaceutically acceptable salts, hydrates, solvates or N-oxidesthereof; (c) a pharmaceutically suitable binder therefor; and (d)optionally, a pharmaceutically acceptable excipient, wherein thepharmaceutical composition is formulated as a solid item adapted forsublingual or buccal administration, the solid item being selected fromthe group consisting of a troche, a lozenge, a capsule, a pill, a cap,and a bolus, to carry out the medical procedure thereby.
 2. The methodof claim 1, wherein the pharmaceutical composition further comprises atherapeutically effective quantity of a third pharmaceutically activecompound selected from the group consisting of β-blockers, antiemeticmedicaments, NSAIDs, antihistamines, α-2-adrenergic agonists, and painrelievers and combinations thereof, or pharmaceutically acceptablesalts, hydrates, solvates or N-oxides thereof.
 3. The method of claim 2,wherein the β-blocker, the α-2-adrenergic agonist or the pain relieveris selected from the group consisting of metoprolol, propranolol,acebutolol, nadolol, atenolol, betaxolol, esmolol, bisoprolol fumarate,carvedilol, nebivolol, penbutolol, timolol, sotalol, dexmedetomidinehydrochloride, and acetaminophen.
 4. The method of claim 2, wherein theantiemetic medicament is selected from the group consisting ofondansentron, dolasetron, granisetron, palonosetron, promethazine,imenhydrinate, and meclizine.
 5. The method of claim 2, wherein theNSAID is selected from the group consisting of bromfenac, ketorolac,etodolac, sulindac, diclofenac, aceclofenac, nepafenac, tolmetin,indomethacin, nabumetone, ketoprofen, dexketoprofen, ibuprofen,flurbiprofen, dexibuprofen, fenoprofen, loxoprofen, oxaprozin, naproxen,aspirin, salicylic acid, diflunisal, salsalate, mefenamic acid,meclofenamic acid, flufenamic acid, tolfenamic acid, meloxicam,piroxicam, ternoxicam, droxicam, lornoxicam, isoxicam, celecoxib,rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib,nimesulide, clonixin, and licofelone.
 6. The method of claim 2, whereinthe antihistamine is selected from the group consisting of hydroxyzinepamoate, hydroxyzine hydrochloride, diphenhydramine hydrochloride,meclizine, chlorpheniramine, clemastine, promethazine, andprochlorperazine.
 7. The method of claim 2, wherein the pharmaceuticalcomposition further comprises a therapeutically effective quantity of areceptor antagonist to benzodiazepines.
 8. The method of claim 7,wherein the receptor antagonist is flumazenil.
 9. The method of claim 2,wherein the first pharmaceutically active compound is medazolam, thesecond pharmaceutically active compound is ketamine and the thirdpharmaceutically active compound is metoprolol, and wherein themedazolam:ketamine:metoprolol ratio is between about 1:2:1 and about1:10:1 by mass.
 10. The pharmaceutical composition of claim 2, whereinthe first pharmaceutically active compound is medazolam, the secondpharmaceutically active compound is ketamine and the thirdpharmaceutically active compound is ondansentron, wherein themedazolam:ketamine:ondansentron ratio is about 3:25:2 by mass.
 11. Themethod of claim 1, wherein the solid item is a troche.
 12. The method ofclaim 1, wherein the binder comprises a polyglycol selected from thegroup consisting of polyethylene glycol, polyethylene oxide,methoxypolyethylene glycol, polypropylene glycol and polybutyleneglycol, or derivatives thereof, having a molecular weight that issufficient to provide suitable hardness and time for dissolution of thetroche.
 13. The method of claim 12, wherein the excipient comprises amember selected from the group consisting of gelatin, sodium saccharin,stevioside, peppermint oil, any natural or artificial fruit, vegetable,flower, beverage or candy flavor, and combinations thereof.
 14. Themethod of claim 1, wherein the binder comprises a product having amolecular weight that is sufficient to provide the necessary hardnessand time for dissolution of the solid item, the binder being selectedfrom the group consisting of methoxypolyethylene glycol, polypropyleneglycol, polybutylene glycol, PEG-laureates, PEG-dilaureates,PEG-oleates, PEG-dioleates, PEG-trioleates, PEG-stearates,PEG-distearates, castor oil derivatives of PEG, palm kernel oilderivatives of PEG, corn oil derivatives of PEG, soya oil derivatives ofPEG, cholesterol derivatives of PEG, phytosterol derivatives of PEG,caprate/caprylate glycerides derivatives of PEG, tocopheryl succinatederivatives of PEG, octylpheno derivatives of PEG, nonylphenolderivatives of PEG, polyglyceryl-10-laurate, polyglyceryl-10-oleate,POE-lauryl ethers, POE-oleyl ethers, POE-stearyl ethers, polysorbates,onostearate, monolaurate and monopalmitate derivatives of sucrose, andproducts of poly(oxypropylene)-co-poly(propylene oxide) family.
 15. Themethod of claim 1, wherein the medical procedure is selected from thegroup consisting of an ophthalmic surgery, a dental procedure, anoutpatient medical procedure, an obstetric or gynecological procedure, agastrointestinal procedure, an otolaryngological procedure, a cosmeticsurgery procedure, a dermatological procedure, a podiatric procedure, anorthopedic procedure, an emergency medical treatment, a psychiatrictreatment, a urological procedure and a veterinarian procedure.
 16. Themethod of claim 15, wherein the ophthalmic surgery is selected from thegroup consisting of cataract surgery, glaucoma surgery, corneal surgery,eyelid surgery, and retinal surgery.
 17. The method of claim 15, whereinthe dental procedure is selected from the group consisting of a toothextraction, oral surgery, and root canal surgery.
 18. The method ofclaim 15, wherein the outpatient surgical procedure is selected from thegroup consisting of a medical imaging procedure, a biopsy, bone marrowharvesting, colonoscopy, endoscopy, and a laparoscopic procedure. 19.The method of claim 15, wherein the pharmaceutical composition isadministered to induce conscious sedation or pre-sedation in a patientin need thereof.
 20. The method of claim 19, wherein the patientexperiences or expects to experience high anxiety, bouts of panicattacks, disquietude, apprehension, or angst prior to, or during, themedical procedure.
 21. A method for carrying out a medical procedure,comprising orally administering to a patient in need of conscioussedation, procedural sedation, analgesia and/or pre-sedation apharmaceutical composition as the first step of the procedure, thepharmaceutical composition comprising: (a) a therapeutically effectivequantity of a first pharmaceutically active compound selected from thegroup consisting of midazolam, diazepam, lorazepam, flunitrazepam,alprazolam, chlordiazepoxide, clonazepam and clorazepate, andpharmaceutically acceptable salts, hydrates, solvates or N-oxidesthereof; (b) a therapeutically effective quantity of a secondpharmaceutically active compound selected from the group consisting ofketamine, dextrorphan, etomidate, methadone, memantine, amantadine,dextromethorphan, and pharmaceutically acceptable salts, hydrates,solvates or N-oxides thereof; and (c) optionally, a pharmaceuticallyacceptable excipient, wherein the pharmaceutical composition isformulated as a liquid item adapted for sublingual or buccaladministration, to carry out the medical procedure thereby.